A major problem with patients who have orthopedic implant devices or joint prosthesis, such as hip replacements, is that many of these begin to fail after five years or so from the time that they are inserted. The failure rate increases exponentially with time so that many patients with an aging hip prosthesis (10 to 15 years), experience pain at the site of the implant and eventually require revision to the original procedure. Although initially this was considered to be a result of fragmentation of the cement substances utilized in older hip prostheses, the problem continues to be observed even in the newer devices which do not rely on the use of cement. A hallmark of these patients is that at the time they develop pain and loosening of the joint they have markedly increased bone turnover, especially bone resorption, in the bone immediately adjacent to the implant. Evidence for this bone turnover can be seen from the fact that bone scanning agents, which are bisphosphonates tagged with technetium, are often taken up at very high concentrations in these areas indicating that there may well be significant targeting of bisphosphonates to the periprosthetic bone.
There is a need in the art for localized controlled/extended release dosage forms of bone growth promotant since in the United States, there are approximately 5 million fractures and 265,000 prosthetic implants per year. Of this population, there is about a 20-30% failure rate within five years of the operation, requiring a repeat surgery and device implant.
Normal bones are living tissues which undergo constant resorption and new bone formation, with the net effect of maintenance of a constant mineral balance. The dual process is commonly called "bone turnover". In normal growing bones, the mineral deposition exceeds the mineral resorption, whereas in certain pathological conditions, bone resorption exceeds bone deposition, for instance due to malignancy or primary hyperparathyroidism, or in osteoporosis. In other pathological conditions the deposition of new bone may take place in undesirable amounts and areas leading to e.g. heterotopic ossification, osteosclerosis, and Paget's disease which is a combination of an abnormal high bone resorption followed by an abnormal calcium deposition. With orthopedic implants, bone resorption may occur at an accelerated rate in the periprosthetic area leading to net bone loss.
Most of the currently available therapeutic agents for the treatment of osteoporosis, e.g. estrogens, act by reducing bone resorption in the osteoporotic patient. See the review article, "British Medical Bulletin" 46 (1), p. 94-112 (1990).
Bisphosphonates are also known in the art as bone resorption inhibitors.
Alendronate, 4-amino-1-hydroxybutylidene-1,1 -bisphosphonic acid monosodium trihydrate is a known bone resorption inhibitor and is described in U.S. Pat. Nos. 4,922,007 and 5,019,651 (Merck).
Clodronate, (dichloromethylene)bisphosphonic acid disodium salt (Proctor and Gamble, is described in Belgium Patent 672,205 (1966) and its preparation is found in J. Org. Chem 32, 4111 (1967).
Tiludronate, ([(4-chlorophenyl)thiomethylene]-bisphosphonic acid) (Sanofi) is described in U.S. Pat. No. 4,876,248 issued Oct. 24, 1989.
YM 175 ([(cycloheptylamino)methylene]bisphosphonic acid, disodium salt) by Yamanouchi is described in U.S. Pat. No. 4,970,335 issued Nov. 13, 1990.
BM 21.0995 (1-Hydroxy-3-(methylpentylamino)-propylidene-bisphosphonate) by Boehringer-Mannheim--is described in U.S. Pat. No. 4,927,814 issued May 22, 1990.
A study by Proctor and Gamble (Norwich Eaton Pharmaceuticals) using risedronate, whose chemical name is sodium trihydrogen [1-hydroxy-2-(3-pyridinyl)ethylidene]bisphosphonate, in combination with estrogen showed a positive effect on bone loss in ovariectomized rats (published in Abstracts 731 and 732 at the Fall 1992 ASBMR meeting in Minn.).
The article, "J. Clin. Invest.", January 1992, 89 (1), p. 74-78 by J. Chow et al., describes the effect of estrogen on ovariectomized rats in which bone resorption was suppressed by pamidronate whose chemical name is 3-amino-1-hydroxy propylidene-bisphosphonic acid disodium salt. They concluded that estrogen inhibits bone resorption and also stimulates bone formation.
Another Proctor and Gamble compound, piridronate, [2-(2-pyridinyl)ethylidene]-bisphosphonic acid, monosodium salt is described in U.S. Pat. No. 4,761,406 as having bone resorption inhibition activity.
The article, "Monatschefte" 99, 2016 (1968) by F. Kasparet describes the synthesis of etidronate, (1-hydroxyethylidene)-bisphosphonic acid, disodium salt, (Proctor and Gamble).
However, the above cited art does not suggest or describe the use of a bisphosphonate in situations to specifically prevent bone resorption in the periprosthetic bone area of an orthopedic implant device.
What is desired in the art is a therapy to optimally treat the bone resorption in the periprosthetic area of an implant device i.e., the bone area which is in contact and close proximity to the device implant, to retard the loosening of the device and to alleviate the pain associated with this condition.